Amphetamine

Identification

Name

Amphetamine

Accession Number

DB00182 (APRD00480)

Type

Small Molecule

Groups

Approved, Illicit, Investigational

Description

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. By mimicking the structures of the catecholamine neurotransmitters, noradrenaline and dopamine, amphetamines modulate monoamine release, reuptake, and signalling within the brain. Although "amphetamine" is used as a descriptor of its own structural class, amphetamine properly refers to a racemic free base composed of equal parts of its two optical antipodes: levo-amphetamine and dextro-amphetamine. Used in the past for the treatment of depression, stress, and for concentration improvement, it is currently available as a prescription drug for the treatment of attention hyperactivity disorder (ADHD), narcolepsy, and as an adjunct in the treatment of exogenous obesity. Amphetamine is also available in a mixed salt/mixed enantiomer form (Adderall), where d-amphetamine and l-amphetamine are available in a ratio of 3:1. It is also available in a prodrug form as lisdexamfetamine.

Pharmacology

Indication

For treatment of Attention Deficit Disorder with Hyperactivity (ADDH), narcolepsy, and exogenous obesity as a short term (a few weeks) adjunct in a regimen of weight reduction based on caloric restriction for patients refractory to alternative therapy.

Amphetamines stimulate the release of norepinephrine from central adrenergic receptors. At higher dosages, they cause release of dopamine from the mesocorticolimbic system and the nigrostriatal dopamine systems. Amphetamine may also act as a direct agonist on central 5-HT receptors and may inhibit monoamine oxidase (MAO). In the periphery, amphetamines are believed to cause the release of noradrenaline by acting on the adrenergic nerve terminals and alpha- and beta-receptors. Modulation of serotonergic pathways may contribute to the calming affect. The drug interacts with VMAT enzymes to enhance release of DA and 5-HT from vesicles. It may also directly cause the reversal of DAT and SERT.

Amphetamine forms easily absorbed molecules that are highly lipid soluble. D-amphetamine mean peak plasma concentrations of 44.9 ng/mL occurred at a median time of 5.0 hours after dosing, and L-amphetamine mean peak plasma concentrations of 14.5 ng/mL occurred at a median time of 5.25 hours after dosing.

Volume of distribution

Not Available

Protein binding

15-40%

Metabolism

Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility.

With normal urine pHs, approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30-40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9 .9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion.

Half life

The half life for adults in the fasted state was found to be 11.25 hr.

Clearance

Not Available

Toxicity

LD50=180 mg/kg(subcutaneous injection in rat). The most common presenting symptoms seen are agitation, hallucinations, suicidal behaviour, and chest pain.